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Malignant Neoplasms of the Oropharynx
10 Malignant Neoplasms of the Oropharynx ■ James S. Lewis, Jr.
■ SQUAMOUS CELL CARCINOMA Squamous cell carcinoma (SCC) arises not only from the surface epithelium of the oropharynx but also from the tonsillar crypts. It is steadily increasing in incidence due to high-risk human papillomavirus (HPV), and HPVpositive oropharyngeal SCC is a biologically and clinically distinct type of head and neck cancer.
CLINICAL FEATURES SCC constitutes the majority of oropharyngeal malignancies (> 90%). Most develop in white men (male to female, 3 : 1) between the ages of 55 and 60 years. Unlike for most other types of head and neck carcinoma, which are declining, the rate of oropharyngeal SCC is increasing dramatically (as much as 5% per year) due to HPV, particularly type 16. It is a global problem but is most important in the United States, Canada, and parts of Northern Europe, where as many as 80% of oropharyngeal SCCs are HPV-positive. The virus is sexually transmitted. Patients have histories of more sex partners and more oral sex exposure than HPV-negative patients. HPV-positive SCC patients are approximately 5 years younger, on average. Carcinogen exposure, diet, and preexisting medical conditions all also play a role in tumor development. Smoking (tobacco) exposure is less important in oropharyngeal than in oral and laryngeal SCC. More than 95% of patients with HPV-negative oropharyngeal SCC are smokers, whereas 60% to 75% of HPV-positive oropharyngeal SCC are current or former smokers, with less exposure overall. Oropharyngeal carcinomas classically present as small primary tumors usually arising from the palatine tonsils followed by the base of the tongue. These sites harbor a large amount of lymphoid tissue associated with invaginated “crypt” epithelium, for which HPV is tropic. For HPV-positive oropharyngeal SCCs, no obvious precursor 230
SQUAMOUS CELL CARCINOMA—DISEASE FACT SHEET Definition ■ A malignant neoplasm arising from the squamous epithelium of the oropharyngeal surface or tonsillar crypts Incidence and Location ■ Most common malignancy of the oropharynx ■ More than 25,000 cases diagnosed in the United States each year ■ Most common in the palatine tonsils followed by the tongue base Sex, Race, and Age Distribution ■ Males > females (~3 : 1) ■ Higher incidence among whites than blacks ■ Most patients 50-60 years of age Clinical Features ■ Surface mucosa preinvasive lesions can either be leukoplakic (white patch) or erythroplakic (red patch) with varying degrees of dysplasia. HPV-positive examples do not have preinvasive lesions. ■ Invasive carcinomas range from depressed ulcerated lesions to fungating masses; many are small and soft, hidden deep in the tonsillar parenchyma ■ Most patients have cervical lymph node metastases at presentation Prognosis and Treatment ■ Tumor stage has a significant impact on outcome and therapy ■ Primary chemoradiation is the most common treatment approach, with transoral surgical resection used at many centers, particularly for early stage disease. Both are effective treatment types; survival at 5 years is approximately 50% for HPV negative and approximately 80% for HPV positive HPV, Human papillomavirus.
lesions have been identified, probably because the crypt epithelium has a discontinuous basement membrane and may be permissive to early metastasis. HPV-negative SCCs are clinically much more like other head and neck SCC, with fungating or ulcerated masses that may be associated
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FIGURE 10.1 Extensive erythroplakia of the tongue base and posterior oral tongue. (Courtesy of Dr. J. Netterville.)
FIGURE 10.3 Computed tomography scan findings in a patient with metastatic HPV–positive oropharyngeal squamous cell carcinoma. The nodal metastasis is exquisitely cystic with a thin wall. (Courtesy of Dr. A. Langerman.)
imaging, and occasionally positron emission tomography are used to determine the extent of local invasion and presence of metastatic spread to regional lymph nodes or distantly. There are no distinct radiographic findings of primary oropharyngeal SCC, but nodal metastases are often (and characteristically) cystic with thin walls and central necrotic material or fluid (Fig. 10.3). More than 90% of patients have metastases to level II nodes.
FIGURE 10.2 An ulcerated, granular, and friable keratinizing-type squamous cell carcinoma of the base of tongue and extending onto the floor of mouth and lateral tongue.
with leukoplakia or erythroplakia (Figs. 10.1 and 10.2). Approximately 80% to 90% of patients present with spread to regional/cervical lymph nodes. In fact, oropharyngeal SCC not infrequently presents as a clinically undetectable tumor or, after thorough work-up, truly is of “unknown primary.”
PATHOLOGIC FEATURES GROSS FINDINGS
The gross appearance of squamous lesions varies from subtle grayish-white thickening of the mucosa (specifically with keratinizing-type SCC) to large ulcerated, flat, or fungating masses with invasion of local structures. Depending on the degree of desmoplasia and tumor necrosis, the cut surface of invasive tumors ranges from relatively soft and inconspicuous to solid and firm to cystic and friable. MICROSCOPIC FINDINGS
RADIOGRAPHIC FEATURES Radiographic evaluation is primarily used for staging purposes. Computed tomography, magnetic resonance
Dysplasia refers to neoplastic alterations of the surface epithelium prior to invasion of the submucosa. These changes include abnormal cellular organization, increased mitotic activity, and nuclear enlargement
232 SQUAMOUS CELL CARCINOMA—PATHOLOGIC FEATURES Gross Findings ■ Can be ulcerated, flat, or fungating masses but more frequently presents as small, relatively soft, ill-defined submucosal lesions Microscopic Findings Premalignant (Noninvasive) Stage (Dysplasia) ■ For HPV-negative neoplasia, dysplastic cells can be limited to the surface squamous epithelium with abnormal cellular organization and maturation, increased mitotic activity, and nuclear enlargement with pleomorphism Malignant (Invasive) Stage ■ Keratinizing-type SCC: infiltrating nests and cords of cells showing varying degrees of squamous differentiation (pink cytoplasm, intercellular bridges, and keratin pearl formation) ■ Desmoplastic stromal reaction including stromal fibrosis and chronic inflammation ■ Nonkeratinizing-type SCC: large, rounded nests of blue cells with little cytoplasm and hyperchromatic, ovoid nuclei; brisk mitotic activity and little keratinizing maturation which may be haphazardly present and may be at the periphery of the nests ■ Specific variants can be seen, including basaloid, papillary, lymphoepithelial-like (“undifferentiated”), spindle cell, and adenosquamous Fine Needle Aspiration ■ Ranges from atypical squamous cells in a background of keratinous and necrotic cystic debris to clusters of cells with high nuclear to cytoplasmic ratios, inconspicuous nucleoli, and background cyst contents and/or necrotic debris Immunohistochemical Findings ■ Immunoreactivity for epithelial markers (e.g., p40 p63, and cytokeratins 5/6 and 34βE12) ■ p16 positivity (prognostic marker and surrogate marker of HPV-positive SCC): strong and diffuse nuclear and cytoplasmic expression (although patchy staining common when used on fine needle aspiration cytology cell block preparations) Pathologic Differential Diagnosis ■ Keratinizing type SCC: pseudoepitheliomatous hyperplasia, verrucous hyperplasia, necrotizing sialometaplasia ■ Nonkeratinizing type SCC: solid pattern of adenoid cystic carcinoma, high-grade neuroendocrine carcinoma, true basaloid SCC, lymphoma HPV, Human papillomavirus; SCC, squamous cell carcinoma.
with pleomorphism. It is seen in the oropharynx but is applicable only for surface mucosal lesions and is most commonly associated with keratinizing-type (or conventional, usually HPV-negative) SCC. Although terminology varies, pleomorphism limited to the lower third of the epithelium is generally referred to as mild dysplasia, pleomorphism limited to the lower two-thirds as moderate dysplasia, and pleomorphism involving the full thickness as severe dysplasia/carcinoma in situ. However, forms of severe dysplasia certainly can have less than full-thickness atypia, but they usually show very undulating rete with “teardrop”-type arrangement
HEAD AND NECK PATHOLOGY
with the downward pushing rete filled with dysplastic cells with nuclear atypia, hyperchromasia, and increased mitotic activity. With progression, cells invade through the basement membrane. With advanced tumor growth, tumor nests invade skeletal muscle and craniofacial bones and may develop perineural and lymphovascular space invasion. Tumor grade in keratinizing-type SCC varies from well to poorly differentiated, from large, maturing nests, to infiltrative small nests and single cells, although histologic grading is minimally predictive of clinical behavior. Regardless of tumor grade, nests of infiltrating keratinizing type SCC tend to elicit a prominent host fibrotic stromal reaction (desmoplasia) (Fig. 10.4). In contrast, HPV-positive oropharyngeal SCC usually does not involve the surface mucosa at all; instead, early lesions arise from, and appear to line, the crypt epithelium (Fig. 10.5). It adopts a “blue cell” morphology in 65% to 80% of patients, characterized by scant cytoplasm and hyperchromatic nuclei, referred to as “nonkeratinizing” SCC. This type usually lacks surface involvement and has large nests with smooth edges, little or no stromal reaction, and no (or limited) squamous maturation (Figs. 10.6 and 10.7) that, when present, is often at the periphery of the nests. Mitotic activity is brisk. Hybrid types having both keratinizing and nonkeratinizing findings are also occasionally seen (sometimes called “nonkeratinizing with maturation”). Although some early lesions may appear to be “in situ” along the tonsillar crypt epithelium, it has a discontinuous basement membrane so is a poor barrier to spread. As such, there is no morphologically definable in situ carcinoma—the term should be avoided at this anatomic subsite (see Fig. 10.5). Certain variants of SCC depart from the typical appearance of conventional SCC. All of these can occur in the oropharynx as the result of HPV. 1. Papillary SCC is common in the oropharynx and is characterized by prominent exophytic papillae with delicate fibrovascular cores (Fig. 10.8). In contrast to benign squamous papillomas, these papillary fronds are diffusely lined by overtly malignant squamous cells. There is usually a frankly invasive component, and approximately 80% are HPV positive. 2. Basaloid SCC is also relatively common in the oropharynx. It is characterized by expanding lobules of hyperchromatic, round, basaloid cells that have a “jigsaw puzzle” pattern, hyalinized, nodular stroma, and only focal areas of mature squamous differentiation (Fig. 10.9). Approximately 75% to 80% are HPV positive and, when so, they have a very good prognosis. HPV-negative basaloid SCC, in the oropharynx and from other sites, by contrast, is extremely aggressive with high rates of metastasis. 3. Spindle cell (or sarcomatoid) carcinoma is quite uncommon in the oropharynx. It classically presents
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FIGURE 10.4 Invasive keratinizing-type squamous cell carcinoma of the oropharynx showing angulated nests of tumor cells with abundant, eosinophilic cytoplasm, scattered keratin pearls, and prominent stromal desmoplasia.
FIGURE 10.5 Nonkeratinizing squamous cell carcinoma along crypts can mimic in situ carcinoma but should not be diagnosed as such because the crypt epithelium is an ineffective barrier to tumor spread.
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FIGURE 10.6 Nonkeratinizing squamous cell carcinoma of the oropharynx consisting of large sheets of tumor cells with oval nuclei, little cytoplasm, and no obvious maturing squamous differentiation. These findings are typical of human papillomavirus– related oropharyngeal carcinomas.
FIGURE 10.7 A nonkeratinizing squamous cell carcinoma with a sheet-like collection of tumor cells with spindling. Inset: Strong, diffuse, nuclear, and cytoplasmic reactivity with p16 immunohistochemistry.
FIGURE 10.8 Papillary squamous cell carcinoma is defined by the delicate, papillary fronds lined diffusely by full-thickness squamous cell carcinoma, with or without an obviously invasive component.
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FIGURE 10.9 Basaloid squamous cell carcinoma infiltrates as rounded lobules of tumor cells having high nuclear to cytoplasmic ratios. The nests of tumor cells characteristically mold to one another, leaving only thin lines of intervening stroma.
FIGURE 10.10 Adenosquamous carcinoma shows a mixture of squamous cell carcinoma with areas where tumor cells form true glands with punched out spaces, smooth cell edges, and frequent intraluminal mucin.
as an exophytic, bosselated mass and is characterized by sheets of spindled and/or pleomorphic cells, usually admixed with a component of typical invasive squamous carcinoma. Rare oropharyngeal cases are HPV-positive, but the prognostic significance of this variant is unknown. 4. Adenosquamous carcinoma is uncommon in the oropharynx and is defined by the presence of an SCC component admixed with true, rounded glands that are usually, but not always, associated with
mucin production (Fig. 10.10). Many HPV-positive adenosquamous carcinomas have been reported. HPV-positive examples sometimes can have tumor cells with apical cilia, mimicking a benign process. In general, it has a worse prognosis than keratinizing SCC, but when HPV-positive, it is probably favorable, just as with other HPV-positive SCC. 5. Lymphoepithelial-like (or “undifferentiated”) carcinoma is seen in approximately 3% of oropharyngeal carcinomas and morphologically is indistinguishable
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FIGURE 10.11 Lymphoepithelial-like carcinoma consists of sheets and ill-defined nests of cells with moderate cytoplasm, poorly defined cell borders, round nuclei with vesicular chromatin and prominent nucleoli, and a brisk lymphoplasmacytic inflammatory infiltrate.
from the same tumor of the nasopharynx. Histologically, it has poorly defined collections of tumor cells with ill-defined cell borders, round nuclei with prominent nucleoli, and a dense lymphoplasmacytic inflammatory infiltrate (Fig. 10.11). It is almost always HPV-positive in the oropharynx and has a very good prognosis.
ANCILLARY STUDIES FINE NEEDLE ASPIRATION
More than 50% of patients present with cervical metastases, and some do not have an obvious primary lesion. Fine-needle aspiration is effective in establishing a diagnosis of metastatic SCC. Cytologic smears from keratinizing-type SCC are often cellular with both syncytial fragments of large pleomorphic cells as well as singly dispersed cells. These cells characteristically have large nuclei, prominent nucleoli, and dense, pink or orangeophilic (“squamoid”-appearing) cytoplasm on Papanicolaou staining. However, most oropharyngeal SCC are nonkeratinizing. These tumors show sheets and clusters of cells with high nuclear to cytoplasmic ratios, inconspicuous nucleoli, very few single cells, hyperchromatic, overlapping nuclei, and background cyst contents and/or necrotic debris. If the node is cystic, it is recommended to obtain cyst contents but to attempt to sample
the more solid portions of the wall. Material for a cell block preparation is recommended to use for HPV testing, which is prognostic and may help to suggest an oropharyngeal primary site. Liquid-based HPV DNA testing can also be performed. IMMUNOHISTOCHEMICAL FINDINGS
Immunohistochemistry is only rarely necessary for the diagnosis of oropharyngeal SCC and most often arises out of the need to exclude small cell carcinoma or lymphoma, which can also have the “blue cell” appearance. Almost all SCCs express a wide spectrum of cytokeratins (pan-keratin, cytokeratins 5/6, 34βE12) and p63 and/or p40 (diffuse pattern) and lack expression of lymphoid, melanocytic, and neuroendocrine markers. In the oropharynx, p16, a tumor suppressor protein that is aberrantly overexpressed in HPV-related carcinoma cells, is strongly and diffusely expressed in the nuclei and cytoplasm in HPV-related SCC (Figs. 10.12 to 10.14). Given the prognostic significance of HPV in this site, routine p16 immunostaining is recommended for all oropharyngeal SCCs.
DIFFERENTIAL DIAGNOSIS Keratinizing-type oropharyngeal SCCs, just like those at other sites such as the oral cavity and larynx, can
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be mistaken for reactive non-neoplastic squamous proliferations such as pseudoepitheliomatous hyperplasia, radiation-induced atypia, and necrotizing sialometaplasia—a proliferation of metaplastic squamous cells within the ducts and acini of minor salivary glands. These reactive processes are generally preceded by an inciting event (e.g., ulceration, radiation) and, in contrast to SCC, do not display infiltrative growth, stromal desmoplasia, or overtly malignant cytology. At the other extreme, nonkeratinizing SCCs can be confused with other “blue cell” neoplasms such as small cell carcinoma, solid adenoid cystic carcinoma, or lymphoma. In this setting, immunohistochemistry may play a useful role in establishing the diagnosis of carcinoma by demonstrating positive staining for high-molecular-weight cytokeratins and p40 (in a diffuse pattern) and no staining for neuroendocrine or lymphoid markers.
PROGNOSIS AND THERAPY Oropharyngeal SCC has two distinct prognostic types— those related to high-risk HPV and those that are not. Marked overexpression of p16 is an effective surrogate marker for HPV status and is a very strong prognostic marker as an individual test. It should be performed on all new oropharyngeal SCC specimens. Overall 5-year survival for p16-positive cases is approximately 80% compared with 40% to 50% for negative ones. Given the marked differences in behavior, staging systems unique to HPV-positive (p16-positive) oropharyngeal SCC are now recommended. Treatment options are highly variable and depend on many factors, including size and location of the primary tumor, spread to regional lymph nodes or distant sites, and the patient’s ability to tolerate treatment. Primary chemotherapy and radiation is extremely effective because the HPV-positive tumors are very sensitive. However, there is an emerging role for primary surgery due to the development of transoral approaches such as laser or robotic surgery, particularly for early stage SCC and for those with small primary tumors, with decisions on adjuvant radiation (and sometimes chemotherapy) depending on the pathology findings.
■ SMALL CELL CARCINOMA Small cell carcinoma is a malignant neoplasm in which the cells show neuroendocrine differentiation histologically and immunohistochemically. It is also known as high-grade neuroendocrine carcinoma and, although rare in the oropharynx with approximately 30 cases reported in the literature, may be on the rise due to HPV.
CLINICAL FEATURES Small cell carcinomas occur in patients between 50 and 70 years old and are slightly more common in men than women. Patients are almost always smokers, usually current and with heavy use. They present similarly to oropharyngeal SCC, with nodal metastases, many complaining of a neck mass as their primary symptom, but some patients present with throat pain or odynophagia. Paraneoplastic syndromes, such as can be seen in lung small cell carcinomas, are exceedingly rare in tumors from the head and neck. Approximately 10 patients have been described with HPV-positive oropharyngeal small cell carcinoma. Despite otherwise having similar demographics to typical patients, a few of these HPV-positive patients have been nonsmokers of slightly younger age.
PATHOLOGIC FEATURES GROSS FINDINGS
There are no distinct gross findings of oropharyngeal small cell carcinomas. They present similarly to SCC, as SMALL CELL CARCINOMA—DISEASE FACT SHEET Definition ■ A high-grade carcinoma that has neuroendocrine differentiation and aggressive clinical behavior Incidence and Location ■ Oropharyngeal small cell carcinoma is very rare, being more common in the larynx Sex and Age Distribution ■ Common in men ■ Patients between 50 and 70 years old Clinical Features ■ Neck symptoms are present in most patients and are usually the presenting symptom ■ Some patients present with throat pain, odynophagia, or hemoptysis ■ Most patients are smokers, often with heavy exposure Prognosis and Treatment ■ The optimal treatment is with primary chemotherapy and radiation, with surgery reserved for rare, very early stage tumors ■ More than 80% of patients die of widely disseminated disease, generally within 2 years ■ Occasional patients with HPV-related carcinomas have been cured of their disease by primary chemotherapy and radiation HPV, Human papillomavirus.
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FIGURE 10.12 Small cell carcinoma with sheets of markedly basophilic tumor with abundant apoptosis.
FIGURE 10.13 Small cell carcinoma tumor cells have nuclei that are angulated, with tapered or “teardrop” shapes, hyperchromasia, apoptosis, and mitosis.
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A
B
FIGURE 10.14 Immunohistochemistry for pancytokeratin (A) shows dot-like reactivity in small cell carcinoma and chromogranin and synaptophysin (B) are usually expressed.
firm, tan masses involving the surface and underlying tonsillar parenchyma. MICROSCOPIC FINDINGS
The key low-power feature of small cell carcinoma is its “blue cell” appearance. It is arranged in variably sized, and poorly defined, nests. There is frequent necrosis. On
mid and higher power, tumor cells have very high nuclear to cytoplasmic ratios and nuclei are hyperchromatic and angulated. They frequently are drawn out into tapered or “teardrop” shapes, have speckled chromatin, and mold to each other. Apoptosis and mitosis are frequent. Rosettes, which are rounded foci with central areas lacking nuclei, are sometimes seen; in some cases crush artifact may also be seen. Approximately 30% will be combined
240 SMALL CELL CARCINOMA—PATHOLOGIC FEATURES Gross Findings ■ No distinct gross findings; firm, tan masses Microscopic Findings ■ Haphazardly arranged, poorly defined nests of very blue appearing tumor cells ■ Very high nuclear to cytoplasmic ratios with speckled chromatin, nuclear molding and teardrop shapes, abundant apoptosis and mitosis ■ Approximately 30% are mixed with SCC, which can either be keratinizing or nonkeratinizing but is more frequently the latter, especially in HPV-related tumors Immunohistochemical Findings ■ Positive for cytokeratins with dot-like, perinuclear pattern ■ Positive, although variably, for neuroendocrine markers synaptophysin, chromogranin, and CD56 ■ A minority of tumors are positive for TTF-1, which is not specific for lung small cell carcinoma Pathologic Differential Diagnosis ■ Nonkeratinizing SCC ■ Lymphoma ■ Metastatic small cell carcinoma from other sites, such as the lung
HEAD AND NECK PATHOLOGY
aggressive nature, prognostic HPV testing is not clearly indicated in routine clinical practice, and caution should be observed with p16, which is positive in almost all small cell carcinomas, including in lung and other head and neck anatomic subsites, regardless of HPV status.
DIFFERENTIAL DIAGNOSIS The key to the diagnosis is to recognize the subtle neuroendocrine histologic features. This is critical because the main differential diagnosis is nonkeratinizing SCC. Both have the blue tumor appearance and have abundant apoptosis and mitosis. However, nonkeratinizing SCC is a little less haphazardly arranged, and the nuclei are more round to oval without speckled chromatin and without nuclear molding. Small cell carcinoma has angulated, densely hyperchromatic cells, and, although both nonkeratinizing SCC and small cell carcinoma have high nuclear to cytoplasmic ratios, it is even higher in small cell carcinoma. Prominent crush artifact favors small cell carcinoma. Lymphoma is easily excluded by morphology and immunohistochemistry for keratins and lymphoid markers.
HPV, Human papillomavirus; SCC, squamous cell carcinoma.
PROGNOSIS AND THERAPY
with SCC, which can either be nonkeratinizing or keratinizing type.
ANCILLARY STUDIES Immunohistochemistry for cytokeratins is positive, classically with a dot-like, perinuclear staining pattern. The neuroendocrine markers synaptophysin, chromogranin-A, and CD56 are variably positive, although almost all express at least one of these markers. Immunohistochemistry can be positive for p63, although it is usually weak and/ or focal. However, small cell carcinomas are negative for p40. Some tumors are positive for TTF-1, which is not specific for lung small cell carcinoma. Because of their
The prognosis for oropharyngeal small cell carcinoma is poor. The vast majority of patients present with high-stage disease. Patients are treated with radiation and chemotherapy. Although small cell carcinomas, just like their lung counterparts, tend to respond initially to chemotherapy, the disease is rapidly progressive and more than 80% of patients die of distant metastases. Patients with HPV-related tumors do not appear to have a better prognosis, most dying with distant metastases. However, a few of the reported HPV-positive patients have been cured, so there may be a slightly better biology compared to HPV-negative small cell carcinoma patients. SUGGESTED READINGS The complete suggested readings list is available online at ExpertConsult.com.
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SUGGESTED READINGS Squamous Cell Carcinoma 1. Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35. 2. Bishop JA, et al. Use of p40 and p63 immunohistochemistry and human papillomavirus testing as ancillary tools for the recognition of head and neck sarcomatoid carcinoma and its distinction from benign and malignant mesenchymal processes. Am J Surg Pathol. 2014;38:257–264. 3. Bishop JA. Non-squamous variants of human papillomavirus-related head and neck carcinoma. Diagn Histopathol. 2014;20:301–307. 4. Bishop JA, et al. Ciliated HPV-related carcinoma: a well-differentiated form of head and neck carcinoma that can be mistaken for a benign cyst. Am J Surg Pathol. 2015;39:1591–1595. 5. Chaturvedi AK, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294–4301. 6. D’Souza G, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944–1956. 7. Gondim DD, et al. Histologic typing in oropharyngeal squamous cell carcinoma—a 4-year prospective practice study with p16 and high risk HPV mRNA testing correlation. Am J Surg Pathol. 2016;40:1117–1124. 8. Lewis JS Jr. P16 immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2012;6:S75–S82. 9. Masand RP, et al. Adenosquamous carcinoma of the head and neck: relationship to human papillomavirus and review of the literature. Head Neck Pathol. 2011;5:108–116. 10. Mehrad M, et al. Papillary squamous cell carcinoma of the head and neck: clinicopathologic and molecular features with special reference to human papillomavirus. Am J Surg Pathol. 2013;37:1349–1356. 11. O’Sullivan B, et al. HPV-mediated (p16+) oropharyngeal cancer. In: Amin MB, ed. AJCC Cancer Staging Manual. 8th ed. Switzerland: Springer Nature; 2016. 12. Radkay-Gonzalez L, et al. Ciliated adenosquamous carcinoma: expanding the phenotypic diversity of human papillomavirusassociated tumors. Head Neck Pathol. 2016;10:167–175.
13. Singhi A, et al. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer. 2010;116:2166–2173. 14. Singhi AD, et al. Lymphoepithelial-like carcinoma of the oropharynx: a morphologic variant of HPV-related head and neck carcinoma. Am J Surg Pathol. 2010;34:800–805. 15. Westra WH. The changing face of head and neck cacner in the 21st century: the impact of HPV on the epidemiology and pathology of oral cancer. Head Neck Pathol. 2009;3:78–81. 16. Westra WH, et al. Squamous cell carcinoma, HPV-positive. In: El-Naggar A, Chan JKC, et al, eds. Classification of Head and Neck Tumors. 4th ed. World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2017:136–138.
Small Cell Carcinoma 1. Bates T, et al. Small cell neuroendocrine carcinoma of the oropharynx harbouring oncogenic HPV-infection. Head Neck Pathol. 2014;8:127–131. 2. Bishop JA, et al. Human papillomavirus-related small cell carcinoma of the oropharynx. Am J Surg Pathol. 2011;35:1679–1684. 3. Kraft S, et al. HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior. Am J Surg Pathol. 2012;36:321–330. 4. Lewis JS Jr., et al. Squamous and neuroendocrine specific immunohistochemical markers in head and neck squamous cell carcinoma: a tissue microarray study. Head Neck Pathol. 2017; in press. 5. Perez-Ordonez B, et al. Poorly differentiated neuroendocrine carcinoma. In: El-Naggar A, Chan JKC, et al, eds. Classification of Head and Neck Tumors. 4th ed. World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2017:97–98. 6. Westra WH, et al. Squamous cell carcinoma, HPV-positive. In: El-Naggar A, Chan JKC, et al, eds. Classification of Head and Neck Tumors. 4th ed. World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2017:136–138.
■ SQUAMOUS CELL CARCINOMA Squamous cell carcinoma (SCC) arises not only from the surface epithelium of the oropharynx but also from the tonsillar crypts. It is steadily increasing in incidence due to high-risk human papillomavirus (HPV), and HPVpositive oropharyngeal SCC is a biologically and clinically distinct type of head and neck cancer.
CLINICAL FEATURES SCC constitutes the majority of oropharyngeal malignancies (> 90%). Most develop in white men (male to female, 3 : 1) between the ages of 55 and 60 years. Unlike for most other types of head and neck carcinoma, which are declining, the rate of oropharyngeal SCC is increasing dramatically (as much as 5% per year) due to HPV, particularly type 16. It is a global problem but is most important in the United States, Canada, and parts of Northern Europe, where as many as 80% of oropharyngeal SCCs are HPV-positive. The virus is sexually transmitted. Patients have histories of more sex partners and more oral sex exposure than HPV-negative patients. HPV-positive SCC patients are approximately 5 years younger, on average. Carcinogen exposure, diet, and preexisting medical conditions all also play a role in tumor development. Smoking (tobacco) exposure is less important in oropharyngeal than in oral and laryngeal SCC. More than 95% of patients with HPV-negative oropharyngeal SCC are smokers, whereas 60% to 75% of HPV-positive oropharyngeal SCC are current or former smokers, with less exposure overall. Oropharyngeal carcinomas classically present as small primary tumors usually arising from the palatine tonsils followed by the base of the tongue. These sites harbor a large amount of lymphoid tissue associated with invaginated “crypt” epithelium, for which HPV is tropic. For HPV-positive oropharyngeal SCCs, no obvious precursor 230
SQUAMOUS CELL CARCINOMA—DISEASE FACT SHEET Definition ■ A malignant neoplasm arising from the squamous epithelium of the oropharyngeal surface or tonsillar crypts Incidence and Location ■ Most common malignancy of the oropharynx ■ More than 25,000 cases diagnosed in the United States each year ■ Most common in the palatine tonsils followed by the tongue base Sex, Race, and Age Distribution ■ Males > females (~3 : 1) ■ Higher incidence among whites than blacks ■ Most patients 50-60 years of age Clinical Features ■ Surface mucosa preinvasive lesions can either be leukoplakic (white patch) or erythroplakic (red patch) with varying degrees of dysplasia. HPV-positive examples do not have preinvasive lesions. ■ Invasive carcinomas range from depressed ulcerated lesions to fungating masses; many are small and soft, hidden deep in the tonsillar parenchyma ■ Most patients have cervical lymph node metastases at presentation Prognosis and Treatment ■ Tumor stage has a significant impact on outcome and therapy ■ Primary chemoradiation is the most common treatment approach, with transoral surgical resection used at many centers, particularly for early stage disease. Both are effective treatment types; survival at 5 years is approximately 50% for HPV negative and approximately 80% for HPV positive HPV, Human papillomavirus.
lesions have been identified, probably because the crypt epithelium has a discontinuous basement membrane and may be permissive to early metastasis. HPV-negative SCCs are clinically much more like other head and neck SCC, with fungating or ulcerated masses that may be associated
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FIGURE 10.1 Extensive erythroplakia of the tongue base and posterior oral tongue. (Courtesy of Dr. J. Netterville.)
FIGURE 10.3 Computed tomography scan findings in a patient with metastatic HPV–positive oropharyngeal squamous cell carcinoma. The nodal metastasis is exquisitely cystic with a thin wall. (Courtesy of Dr. A. Langerman.)
imaging, and occasionally positron emission tomography are used to determine the extent of local invasion and presence of metastatic spread to regional lymph nodes or distantly. There are no distinct radiographic findings of primary oropharyngeal SCC, but nodal metastases are often (and characteristically) cystic with thin walls and central necrotic material or fluid (Fig. 10.3). More than 90% of patients have metastases to level II nodes.
FIGURE 10.2 An ulcerated, granular, and friable keratinizing-type squamous cell carcinoma of the base of tongue and extending onto the floor of mouth and lateral tongue.
with leukoplakia or erythroplakia (Figs. 10.1 and 10.2). Approximately 80% to 90% of patients present with spread to regional/cervical lymph nodes. In fact, oropharyngeal SCC not infrequently presents as a clinically undetectable tumor or, after thorough work-up, truly is of “unknown primary.”
PATHOLOGIC FEATURES GROSS FINDINGS
The gross appearance of squamous lesions varies from subtle grayish-white thickening of the mucosa (specifically with keratinizing-type SCC) to large ulcerated, flat, or fungating masses with invasion of local structures. Depending on the degree of desmoplasia and tumor necrosis, the cut surface of invasive tumors ranges from relatively soft and inconspicuous to solid and firm to cystic and friable. MICROSCOPIC FINDINGS
RADIOGRAPHIC FEATURES Radiographic evaluation is primarily used for staging purposes. Computed tomography, magnetic resonance
Dysplasia refers to neoplastic alterations of the surface epithelium prior to invasion of the submucosa. These changes include abnormal cellular organization, increased mitotic activity, and nuclear enlargement
232 SQUAMOUS CELL CARCINOMA—PATHOLOGIC FEATURES Gross Findings ■ Can be ulcerated, flat, or fungating masses but more frequently presents as small, relatively soft, ill-defined submucosal lesions Microscopic Findings Premalignant (Noninvasive) Stage (Dysplasia) ■ For HPV-negative neoplasia, dysplastic cells can be limited to the surface squamous epithelium with abnormal cellular organization and maturation, increased mitotic activity, and nuclear enlargement with pleomorphism Malignant (Invasive) Stage ■ Keratinizing-type SCC: infiltrating nests and cords of cells showing varying degrees of squamous differentiation (pink cytoplasm, intercellular bridges, and keratin pearl formation) ■ Desmoplastic stromal reaction including stromal fibrosis and chronic inflammation ■ Nonkeratinizing-type SCC: large, rounded nests of blue cells with little cytoplasm and hyperchromatic, ovoid nuclei; brisk mitotic activity and little keratinizing maturation which may be haphazardly present and may be at the periphery of the nests ■ Specific variants can be seen, including basaloid, papillary, lymphoepithelial-like (“undifferentiated”), spindle cell, and adenosquamous Fine Needle Aspiration ■ Ranges from atypical squamous cells in a background of keratinous and necrotic cystic debris to clusters of cells with high nuclear to cytoplasmic ratios, inconspicuous nucleoli, and background cyst contents and/or necrotic debris Immunohistochemical Findings ■ Immunoreactivity for epithelial markers (e.g., p40 p63, and cytokeratins 5/6 and 34βE12) ■ p16 positivity (prognostic marker and surrogate marker of HPV-positive SCC): strong and diffuse nuclear and cytoplasmic expression (although patchy staining common when used on fine needle aspiration cytology cell block preparations) Pathologic Differential Diagnosis ■ Keratinizing type SCC: pseudoepitheliomatous hyperplasia, verrucous hyperplasia, necrotizing sialometaplasia ■ Nonkeratinizing type SCC: solid pattern of adenoid cystic carcinoma, high-grade neuroendocrine carcinoma, true basaloid SCC, lymphoma HPV, Human papillomavirus; SCC, squamous cell carcinoma.
with pleomorphism. It is seen in the oropharynx but is applicable only for surface mucosal lesions and is most commonly associated with keratinizing-type (or conventional, usually HPV-negative) SCC. Although terminology varies, pleomorphism limited to the lower third of the epithelium is generally referred to as mild dysplasia, pleomorphism limited to the lower two-thirds as moderate dysplasia, and pleomorphism involving the full thickness as severe dysplasia/carcinoma in situ. However, forms of severe dysplasia certainly can have less than full-thickness atypia, but they usually show very undulating rete with “teardrop”-type arrangement
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with the downward pushing rete filled with dysplastic cells with nuclear atypia, hyperchromasia, and increased mitotic activity. With progression, cells invade through the basement membrane. With advanced tumor growth, tumor nests invade skeletal muscle and craniofacial bones and may develop perineural and lymphovascular space invasion. Tumor grade in keratinizing-type SCC varies from well to poorly differentiated, from large, maturing nests, to infiltrative small nests and single cells, although histologic grading is minimally predictive of clinical behavior. Regardless of tumor grade, nests of infiltrating keratinizing type SCC tend to elicit a prominent host fibrotic stromal reaction (desmoplasia) (Fig. 10.4). In contrast, HPV-positive oropharyngeal SCC usually does not involve the surface mucosa at all; instead, early lesions arise from, and appear to line, the crypt epithelium (Fig. 10.5). It adopts a “blue cell” morphology in 65% to 80% of patients, characterized by scant cytoplasm and hyperchromatic nuclei, referred to as “nonkeratinizing” SCC. This type usually lacks surface involvement and has large nests with smooth edges, little or no stromal reaction, and no (or limited) squamous maturation (Figs. 10.6 and 10.7) that, when present, is often at the periphery of the nests. Mitotic activity is brisk. Hybrid types having both keratinizing and nonkeratinizing findings are also occasionally seen (sometimes called “nonkeratinizing with maturation”). Although some early lesions may appear to be “in situ” along the tonsillar crypt epithelium, it has a discontinuous basement membrane so is a poor barrier to spread. As such, there is no morphologically definable in situ carcinoma—the term should be avoided at this anatomic subsite (see Fig. 10.5). Certain variants of SCC depart from the typical appearance of conventional SCC. All of these can occur in the oropharynx as the result of HPV. 1. Papillary SCC is common in the oropharynx and is characterized by prominent exophytic papillae with delicate fibrovascular cores (Fig. 10.8). In contrast to benign squamous papillomas, these papillary fronds are diffusely lined by overtly malignant squamous cells. There is usually a frankly invasive component, and approximately 80% are HPV positive. 2. Basaloid SCC is also relatively common in the oropharynx. It is characterized by expanding lobules of hyperchromatic, round, basaloid cells that have a “jigsaw puzzle” pattern, hyalinized, nodular stroma, and only focal areas of mature squamous differentiation (Fig. 10.9). Approximately 75% to 80% are HPV positive and, when so, they have a very good prognosis. HPV-negative basaloid SCC, in the oropharynx and from other sites, by contrast, is extremely aggressive with high rates of metastasis. 3. Spindle cell (or sarcomatoid) carcinoma is quite uncommon in the oropharynx. It classically presents
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FIGURE 10.4 Invasive keratinizing-type squamous cell carcinoma of the oropharynx showing angulated nests of tumor cells with abundant, eosinophilic cytoplasm, scattered keratin pearls, and prominent stromal desmoplasia.
FIGURE 10.5 Nonkeratinizing squamous cell carcinoma along crypts can mimic in situ carcinoma but should not be diagnosed as such because the crypt epithelium is an ineffective barrier to tumor spread.
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FIGURE 10.6 Nonkeratinizing squamous cell carcinoma of the oropharynx consisting of large sheets of tumor cells with oval nuclei, little cytoplasm, and no obvious maturing squamous differentiation. These findings are typical of human papillomavirus– related oropharyngeal carcinomas.
FIGURE 10.7 A nonkeratinizing squamous cell carcinoma with a sheet-like collection of tumor cells with spindling. Inset: Strong, diffuse, nuclear, and cytoplasmic reactivity with p16 immunohistochemistry.
FIGURE 10.8 Papillary squamous cell carcinoma is defined by the delicate, papillary fronds lined diffusely by full-thickness squamous cell carcinoma, with or without an obviously invasive component.
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FIGURE 10.9 Basaloid squamous cell carcinoma infiltrates as rounded lobules of tumor cells having high nuclear to cytoplasmic ratios. The nests of tumor cells characteristically mold to one another, leaving only thin lines of intervening stroma.
FIGURE 10.10 Adenosquamous carcinoma shows a mixture of squamous cell carcinoma with areas where tumor cells form true glands with punched out spaces, smooth cell edges, and frequent intraluminal mucin.
as an exophytic, bosselated mass and is characterized by sheets of spindled and/or pleomorphic cells, usually admixed with a component of typical invasive squamous carcinoma. Rare oropharyngeal cases are HPV-positive, but the prognostic significance of this variant is unknown. 4. Adenosquamous carcinoma is uncommon in the oropharynx and is defined by the presence of an SCC component admixed with true, rounded glands that are usually, but not always, associated with
mucin production (Fig. 10.10). Many HPV-positive adenosquamous carcinomas have been reported. HPV-positive examples sometimes can have tumor cells with apical cilia, mimicking a benign process. In general, it has a worse prognosis than keratinizing SCC, but when HPV-positive, it is probably favorable, just as with other HPV-positive SCC. 5. Lymphoepithelial-like (or “undifferentiated”) carcinoma is seen in approximately 3% of oropharyngeal carcinomas and morphologically is indistinguishable
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FIGURE 10.11 Lymphoepithelial-like carcinoma consists of sheets and ill-defined nests of cells with moderate cytoplasm, poorly defined cell borders, round nuclei with vesicular chromatin and prominent nucleoli, and a brisk lymphoplasmacytic inflammatory infiltrate.
from the same tumor of the nasopharynx. Histologically, it has poorly defined collections of tumor cells with ill-defined cell borders, round nuclei with prominent nucleoli, and a dense lymphoplasmacytic inflammatory infiltrate (Fig. 10.11). It is almost always HPV-positive in the oropharynx and has a very good prognosis.
ANCILLARY STUDIES FINE NEEDLE ASPIRATION
More than 50% of patients present with cervical metastases, and some do not have an obvious primary lesion. Fine-needle aspiration is effective in establishing a diagnosis of metastatic SCC. Cytologic smears from keratinizing-type SCC are often cellular with both syncytial fragments of large pleomorphic cells as well as singly dispersed cells. These cells characteristically have large nuclei, prominent nucleoli, and dense, pink or orangeophilic (“squamoid”-appearing) cytoplasm on Papanicolaou staining. However, most oropharyngeal SCC are nonkeratinizing. These tumors show sheets and clusters of cells with high nuclear to cytoplasmic ratios, inconspicuous nucleoli, very few single cells, hyperchromatic, overlapping nuclei, and background cyst contents and/or necrotic debris. If the node is cystic, it is recommended to obtain cyst contents but to attempt to sample
the more solid portions of the wall. Material for a cell block preparation is recommended to use for HPV testing, which is prognostic and may help to suggest an oropharyngeal primary site. Liquid-based HPV DNA testing can also be performed. IMMUNOHISTOCHEMICAL FINDINGS
Immunohistochemistry is only rarely necessary for the diagnosis of oropharyngeal SCC and most often arises out of the need to exclude small cell carcinoma or lymphoma, which can also have the “blue cell” appearance. Almost all SCCs express a wide spectrum of cytokeratins (pan-keratin, cytokeratins 5/6, 34βE12) and p63 and/or p40 (diffuse pattern) and lack expression of lymphoid, melanocytic, and neuroendocrine markers. In the oropharynx, p16, a tumor suppressor protein that is aberrantly overexpressed in HPV-related carcinoma cells, is strongly and diffusely expressed in the nuclei and cytoplasm in HPV-related SCC (Figs. 10.12 to 10.14). Given the prognostic significance of HPV in this site, routine p16 immunostaining is recommended for all oropharyngeal SCCs.
DIFFERENTIAL DIAGNOSIS Keratinizing-type oropharyngeal SCCs, just like those at other sites such as the oral cavity and larynx, can
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be mistaken for reactive non-neoplastic squamous proliferations such as pseudoepitheliomatous hyperplasia, radiation-induced atypia, and necrotizing sialometaplasia—a proliferation of metaplastic squamous cells within the ducts and acini of minor salivary glands. These reactive processes are generally preceded by an inciting event (e.g., ulceration, radiation) and, in contrast to SCC, do not display infiltrative growth, stromal desmoplasia, or overtly malignant cytology. At the other extreme, nonkeratinizing SCCs can be confused with other “blue cell” neoplasms such as small cell carcinoma, solid adenoid cystic carcinoma, or lymphoma. In this setting, immunohistochemistry may play a useful role in establishing the diagnosis of carcinoma by demonstrating positive staining for high-molecular-weight cytokeratins and p40 (in a diffuse pattern) and no staining for neuroendocrine or lymphoid markers.
PROGNOSIS AND THERAPY Oropharyngeal SCC has two distinct prognostic types— those related to high-risk HPV and those that are not. Marked overexpression of p16 is an effective surrogate marker for HPV status and is a very strong prognostic marker as an individual test. It should be performed on all new oropharyngeal SCC specimens. Overall 5-year survival for p16-positive cases is approximately 80% compared with 40% to 50% for negative ones. Given the marked differences in behavior, staging systems unique to HPV-positive (p16-positive) oropharyngeal SCC are now recommended. Treatment options are highly variable and depend on many factors, including size and location of the primary tumor, spread to regional lymph nodes or distant sites, and the patient’s ability to tolerate treatment. Primary chemotherapy and radiation is extremely effective because the HPV-positive tumors are very sensitive. However, there is an emerging role for primary surgery due to the development of transoral approaches such as laser or robotic surgery, particularly for early stage SCC and for those with small primary tumors, with decisions on adjuvant radiation (and sometimes chemotherapy) depending on the pathology findings.
■ SMALL CELL CARCINOMA Small cell carcinoma is a malignant neoplasm in which the cells show neuroendocrine differentiation histologically and immunohistochemically. It is also known as high-grade neuroendocrine carcinoma and, although rare in the oropharynx with approximately 30 cases reported in the literature, may be on the rise due to HPV.
CLINICAL FEATURES Small cell carcinomas occur in patients between 50 and 70 years old and are slightly more common in men than women. Patients are almost always smokers, usually current and with heavy use. They present similarly to oropharyngeal SCC, with nodal metastases, many complaining of a neck mass as their primary symptom, but some patients present with throat pain or odynophagia. Paraneoplastic syndromes, such as can be seen in lung small cell carcinomas, are exceedingly rare in tumors from the head and neck. Approximately 10 patients have been described with HPV-positive oropharyngeal small cell carcinoma. Despite otherwise having similar demographics to typical patients, a few of these HPV-positive patients have been nonsmokers of slightly younger age.
PATHOLOGIC FEATURES GROSS FINDINGS
There are no distinct gross findings of oropharyngeal small cell carcinomas. They present similarly to SCC, as SMALL CELL CARCINOMA—DISEASE FACT SHEET Definition ■ A high-grade carcinoma that has neuroendocrine differentiation and aggressive clinical behavior Incidence and Location ■ Oropharyngeal small cell carcinoma is very rare, being more common in the larynx Sex and Age Distribution ■ Common in men ■ Patients between 50 and 70 years old Clinical Features ■ Neck symptoms are present in most patients and are usually the presenting symptom ■ Some patients present with throat pain, odynophagia, or hemoptysis ■ Most patients are smokers, often with heavy exposure Prognosis and Treatment ■ The optimal treatment is with primary chemotherapy and radiation, with surgery reserved for rare, very early stage tumors ■ More than 80% of patients die of widely disseminated disease, generally within 2 years ■ Occasional patients with HPV-related carcinomas have been cured of their disease by primary chemotherapy and radiation HPV, Human papillomavirus.
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FIGURE 10.12 Small cell carcinoma with sheets of markedly basophilic tumor with abundant apoptosis.
FIGURE 10.13 Small cell carcinoma tumor cells have nuclei that are angulated, with tapered or “teardrop” shapes, hyperchromasia, apoptosis, and mitosis.
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A
B
FIGURE 10.14 Immunohistochemistry for pancytokeratin (A) shows dot-like reactivity in small cell carcinoma and chromogranin and synaptophysin (B) are usually expressed.
firm, tan masses involving the surface and underlying tonsillar parenchyma. MICROSCOPIC FINDINGS
The key low-power feature of small cell carcinoma is its “blue cell” appearance. It is arranged in variably sized, and poorly defined, nests. There is frequent necrosis. On
mid and higher power, tumor cells have very high nuclear to cytoplasmic ratios and nuclei are hyperchromatic and angulated. They frequently are drawn out into tapered or “teardrop” shapes, have speckled chromatin, and mold to each other. Apoptosis and mitosis are frequent. Rosettes, which are rounded foci with central areas lacking nuclei, are sometimes seen; in some cases crush artifact may also be seen. Approximately 30% will be combined
240 SMALL CELL CARCINOMA—PATHOLOGIC FEATURES Gross Findings ■ No distinct gross findings; firm, tan masses Microscopic Findings ■ Haphazardly arranged, poorly defined nests of very blue appearing tumor cells ■ Very high nuclear to cytoplasmic ratios with speckled chromatin, nuclear molding and teardrop shapes, abundant apoptosis and mitosis ■ Approximately 30% are mixed with SCC, which can either be keratinizing or nonkeratinizing but is more frequently the latter, especially in HPV-related tumors Immunohistochemical Findings ■ Positive for cytokeratins with dot-like, perinuclear pattern ■ Positive, although variably, for neuroendocrine markers synaptophysin, chromogranin, and CD56 ■ A minority of tumors are positive for TTF-1, which is not specific for lung small cell carcinoma Pathologic Differential Diagnosis ■ Nonkeratinizing SCC ■ Lymphoma ■ Metastatic small cell carcinoma from other sites, such as the lung
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aggressive nature, prognostic HPV testing is not clearly indicated in routine clinical practice, and caution should be observed with p16, which is positive in almost all small cell carcinomas, including in lung and other head and neck anatomic subsites, regardless of HPV status.
DIFFERENTIAL DIAGNOSIS The key to the diagnosis is to recognize the subtle neuroendocrine histologic features. This is critical because the main differential diagnosis is nonkeratinizing SCC. Both have the blue tumor appearance and have abundant apoptosis and mitosis. However, nonkeratinizing SCC is a little less haphazardly arranged, and the nuclei are more round to oval without speckled chromatin and without nuclear molding. Small cell carcinoma has angulated, densely hyperchromatic cells, and, although both nonkeratinizing SCC and small cell carcinoma have high nuclear to cytoplasmic ratios, it is even higher in small cell carcinoma. Prominent crush artifact favors small cell carcinoma. Lymphoma is easily excluded by morphology and immunohistochemistry for keratins and lymphoid markers.
HPV, Human papillomavirus; SCC, squamous cell carcinoma.
PROGNOSIS AND THERAPY
with SCC, which can either be nonkeratinizing or keratinizing type.
ANCILLARY STUDIES Immunohistochemistry for cytokeratins is positive, classically with a dot-like, perinuclear staining pattern. The neuroendocrine markers synaptophysin, chromogranin-A, and CD56 are variably positive, although almost all express at least one of these markers. Immunohistochemistry can be positive for p63, although it is usually weak and/ or focal. However, small cell carcinomas are negative for p40. Some tumors are positive for TTF-1, which is not specific for lung small cell carcinoma. Because of their
The prognosis for oropharyngeal small cell carcinoma is poor. The vast majority of patients present with high-stage disease. Patients are treated with radiation and chemotherapy. Although small cell carcinomas, just like their lung counterparts, tend to respond initially to chemotherapy, the disease is rapidly progressive and more than 80% of patients die of distant metastases. Patients with HPV-related tumors do not appear to have a better prognosis, most dying with distant metastases. However, a few of the reported HPV-positive patients have been cured, so there may be a slightly better biology compared to HPV-negative small cell carcinoma patients. SUGGESTED READINGS The complete suggested readings list is available online at ExpertConsult.com.
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SUGGESTED READINGS Squamous Cell Carcinoma 1. Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35. 2. Bishop JA, et al. Use of p40 and p63 immunohistochemistry and human papillomavirus testing as ancillary tools for the recognition of head and neck sarcomatoid carcinoma and its distinction from benign and malignant mesenchymal processes. Am J Surg Pathol. 2014;38:257–264. 3. Bishop JA. Non-squamous variants of human papillomavirus-related head and neck carcinoma. Diagn Histopathol. 2014;20:301–307. 4. Bishop JA, et al. Ciliated HPV-related carcinoma: a well-differentiated form of head and neck carcinoma that can be mistaken for a benign cyst. Am J Surg Pathol. 2015;39:1591–1595. 5. Chaturvedi AK, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294–4301. 6. D’Souza G, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944–1956. 7. Gondim DD, et al. Histologic typing in oropharyngeal squamous cell carcinoma—a 4-year prospective practice study with p16 and high risk HPV mRNA testing correlation. Am J Surg Pathol. 2016;40:1117–1124. 8. Lewis JS Jr. P16 immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2012;6:S75–S82. 9. Masand RP, et al. Adenosquamous carcinoma of the head and neck: relationship to human papillomavirus and review of the literature. Head Neck Pathol. 2011;5:108–116. 10. Mehrad M, et al. Papillary squamous cell carcinoma of the head and neck: clinicopathologic and molecular features with special reference to human papillomavirus. Am J Surg Pathol. 2013;37:1349–1356. 11. O’Sullivan B, et al. HPV-mediated (p16+) oropharyngeal cancer. In: Amin MB, ed. AJCC Cancer Staging Manual. 8th ed. Switzerland: Springer Nature; 2016. 12. Radkay-Gonzalez L, et al. Ciliated adenosquamous carcinoma: expanding the phenotypic diversity of human papillomavirusassociated tumors. Head Neck Pathol. 2016;10:167–175.
13. Singhi A, et al. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer. 2010;116:2166–2173. 14. Singhi AD, et al. Lymphoepithelial-like carcinoma of the oropharynx: a morphologic variant of HPV-related head and neck carcinoma. Am J Surg Pathol. 2010;34:800–805. 15. Westra WH. The changing face of head and neck cacner in the 21st century: the impact of HPV on the epidemiology and pathology of oral cancer. Head Neck Pathol. 2009;3:78–81. 16. Westra WH, et al. Squamous cell carcinoma, HPV-positive. In: El-Naggar A, Chan JKC, et al, eds. Classification of Head and Neck Tumors. 4th ed. World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2017:136–138.
Small Cell Carcinoma 1. Bates T, et al. Small cell neuroendocrine carcinoma of the oropharynx harbouring oncogenic HPV-infection. Head Neck Pathol. 2014;8:127–131. 2. Bishop JA, et al. Human papillomavirus-related small cell carcinoma of the oropharynx. Am J Surg Pathol. 2011;35:1679–1684. 3. Kraft S, et al. HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior. Am J Surg Pathol. 2012;36:321–330. 4. Lewis JS Jr., et al. Squamous and neuroendocrine specific immunohistochemical markers in head and neck squamous cell carcinoma: a tissue microarray study. Head Neck Pathol. 2017; in press. 5. Perez-Ordonez B, et al. Poorly differentiated neuroendocrine carcinoma. In: El-Naggar A, Chan JKC, et al, eds. Classification of Head and Neck Tumors. 4th ed. World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2017:97–98. 6. Westra WH, et al. Squamous cell carcinoma, HPV-positive. In: El-Naggar A, Chan JKC, et al, eds. Classification of Head and Neck Tumors. 4th ed. World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2017:136–138.